A mutant SV40 large T antigen interferes with nuclear localization of a heterologous protein

Schneider, Jens; Schindewolf, Catherine; Zee, Karen van; Fanning, Ellen

doi:10.1016/0092-8674(88)90185-7

Cited by 30 publications

(33 citation statements)

References 41 publications

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“…We hypothesize that AHC mutations induce a misfolded conformation of the DAX-1 C terminus, which exposes new molecular surfaces able to interact with cytoplasmic anchoring sites. This notion is reminiscent of the case of a simian virus 40 large T antigen frameshift mutant that is cytoplasmic even in the presence of an intact NLS, because of the presence of multiple hydrophobic residues in its novel C terminus (40). The nature of the cytoplasmic sites of interaction for DAX-1 AHC mutants is at the moment unknown.…”

Section: Discussionmentioning

confidence: 97%

X-linked adrenal hypoplasia congenita is caused by abnormal nuclear localization of the DAX-1 protein

Lehmann

Lalli

Sassone–Corsi

2002

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the DAX-1 [dosage-sensitive sex reversal-adrenal hypoplasia congenita (AHC) critical region on the X chromosome; NR0B1] gene cause X-linked AHC associated with hypogonadotropic hypogonadism. DAX-1 encodes an unusual orphan member of the nuclear hormone receptor superfamily, acting as a transcriptional repressor of genes involved in the steroidogenic pathway. All DAX-1 mutations found in AHC patients alter the protein C terminus, which shares similarity to the ligand binding domain of nuclear hormone receptors and bears transcriptional repressor activity. This property is invariably impaired in DAX-1 AHC mutants. Here we show that the localization of DAX-1 AHC mutant proteins is drastically shifted toward the cytoplasm, even if their nuclear localization signal, which resides in the N terminal of the protein, is intact. Cytoplasmic localization of DAX-1 AHC mutants correlates with an impairment in their transcriptional repression activity. These results reveal a critical role of an intact C terminus in determining DAX-1 subcellular localization and constitute an important example of a defect in human organogenesis caused by impaired nuclear localization of a transcription factor. A drenal hypoplasia congenita (AHC) is an inherited disorder of the adrenal cortex commonly manifested as an earlyonset adrenal insufficiency syndrome. Two different forms of this disease have been recognized: a X-linked form and a rare autosomal recessive or sporadic form (1). AHC is a lethal disease if untreated, mainly because of mineralocorticoid deficit. Although it can present a wide clinical spectrum (1-3), a constant feature of the X-linked syndrome is the association with hypogonadotropic hypogonadism (HHG). It has been shown that HHG is caused by combined hypothalamic failure in gonadotropin-releasing hormone release and pituitary defect in gonadotropin production (2). Mutations in the DAX-1 (dosagesensitive sex reversal-AHC critical region on the X chromosome gene 1; NR0B1) gene, situated in Xp21, are responsible for the X-linked form of AHC͞HHG (4, 5).DAX-1 encodes an unusual orphan member of the nuclear hormone receptor superfamily (4-7) whose expression is restricted to the adrenal cortex, testis, ovary, pituitary gonadotropes, and hypothalamic ventromedial nucleus (8,9). This pattern of expression closely matches the characteristics of the disease and suggests that DAX-1 also plays a role in reproductive function. Strikingly, inactivation of the mouse Ahch homologue does not produce adrenal hypoplasia, but male sterility caused by progressive testicular seminiferous tubules degeneration (10). Other links with reproductive function and phenotypical sex determination are provided by the findings that the DAX-1 gene lies inside the critical region on the X chromosome whose duplication causes dosage-sensitive sex reversal in XY individuals (11,12), and that overexpression of DAX-1 in particular mouse strains causes phenotypical sex reversal (13). Furthermore, mouse Dax-1 has been shown to antagonize the synergisti...

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Section: Discussionmentioning

confidence: 97%

X-linked adrenal hypoplasia congenita is caused by abnormal nuclear localization of the DAX-1 protein

Lehmann

Lalli

Sassone–Corsi

2002

Proc. Natl. Acad. Sci. U.S.A.

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“…20 Similar mis-transport has been demonstrated for transcription factors involved in oncogenesis such as c-Fos and SV40 large T antigen. [23][24][25] We have previously demonstrated aberrant localization of F1␤ ATPase, the catalytic subunit of mitochondrial ATP synthase, to the plasma membrane of tumor cell lines. 8 This observation was confirmed and extended in another report that demonstrated both F1␤-and F1␣-ATPase on the surface of the A549 tumor cell line and growth factor-supplemented cultured human endothelial cells.…”

Section: Semiquantitative Analysis Of P385 Gene Transcriptionmentioning

confidence: 99%

Genetic identity and differential expression of p38.5 (Haymaker) in human malignant and nonmalignant cells

et al. 2001

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Previous studies from our laboratory revealed a novel protein of 38.5 kD on the surface of malignant cell lines of hematopoetic origin that exhibit susceptibility to naive natural killer (NK) cell-mediated lysis. In contrast, p38.5 was not detected on the surface of NK cell-resistant carcinoma cell lines or normal cells. We now report that this protein is differentially expressed, intracellularly, in malignant cell lines of both hematopoetic and epithelial origin compared with nonmalignant cells. To characterize p38.5 further, we used a previously developed antipeptide antibody (anti-11-mer) to probe cDNA expression libraries and subsequently per-

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“…Mutant forms of BRCA1 that occur in breast and ovarian cancer localize, however, to the cytoplasm (Chen et al 1995). Similar mistransport has been demonstrated for transcription factors involved in oncogenesis, such as c-Fos and SV40 large T antigen (Schneider et al 1988;Roux et al 1990;Moll et al 1991). Haymaker was overexpressed in all malignant cell lines studied thus far.…”

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confidence: 87%

Haymaker Gene Expression in Malignant and Normal Gynecologic Tissues

Borowsky

Das

Axiotis

et al. 2006

J Histochem Cytochem.

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We previously reported that cell lines established from human carcinomas and leukemias/lymphomas expressed high levels of an intracellular membrane-bound protein, Haymaker, whereas cell lines derived from non-malignant connective tissue cells and lymphoid cells expressed low levels of this gene product. To determine whether these findings reflect neoplastic transformation or, alternatively, tissue specificity, we examined by immunohistochemical and molecular methods the expression of Haymaker in gynecologic organs with and without tumor. A highly specific, affinity-purified rabbit polyclonal antibody against a 25-mer Haymaker peptide was used for immunohistochemical staining and morphometric analysis of 85 tissue specimens. Immunohistochemical studies demonstrate, for the first time, that Haymaker protein is highly expressed in epithelial cells of the endometrium of the normal uterus and to a somewhat lesser extent in the mucosa of the normal vagina and cervix, but is poorly expressed or absent in cells of the connective tissue and smooth muscle strata of these organs ( p < 0.005). Significant differences in Haymaker expression, as assessed by immunohistochemistry, between malignant and normal gynecologic tissues were not observed ( p = 0.27). The expression of Haymaker protein does not appear, therefore, to be a marker of malignant transformation of the epithelium of gynecologic organs but rather distinguishes both normal and malignant epithelial cells from normal connective tissue and smooth muscle cells

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A mutant SV40 large T antigen interferes with nuclear localization of a heterologous protein

Cited by 30 publications

References 41 publications

X-linked adrenal hypoplasia congenita is caused by abnormal nuclear localization of the DAX-1 protein

X-linked adrenal hypoplasia congenita is caused by abnormal nuclear localization of the DAX-1 protein

Genetic identity and differential expression of p38.5 (Haymaker) in human malignant and nonmalignant cells

Haymaker Gene Expression in Malignant and Normal Gynecologic Tissues

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